Infrastructure for the ClinSeq Project A phase I cohort of 1,500 individuals has been evaluated at the NIH Clinical Research Center for a set of cardiovascular phenotypic features, including, but not limited to, coronary artery calcification, lipid profiles, and blood pressure. Participants were selected to fall within a spectrum of coronary artery calcification from normal to disease phenotype. Participants underwent a clinical evaluation, targeted clinical tests, and blood sample collection for genomic analysis and they will provide baseline information about pertinent health behavior and a family history. Exome sequencing of peripheral blood DNA has been performed on all 1,500. Importantly, ClinSeq(c) subjects are consented for return of results (both research and clinical results) and for re-contact for iterative phenotyping. ClinSeq(c) was designed in a way that will provide the long-term potential for pursuing many different clinical projects. We propose to select subsets of subjects from the ClinSeq(c) dataset, identified by their genomic attributes, explore their phenotypic manifestations, as a new path to understanding genotype-phenotype relationships. Furthermore, we have opened a new phase of recruitment, ClinSeq Phase II, which targets African Americans, a group that is underrepresented in clinical genomics research. By committing to focused recruitment in the community, we have reached our targeted goal of 500. Piloting large-scale medical sequencing (LSMS) in a clinical research setting. We have made excellent progress in this area over the last year and are continuing to push forward in this arena. These studies required the development of the capacity to screen exomes for hundreds to thousands of variants, filter them for analytic and clinical validity, and integrate them with clinical data. To continue and expand this work, we have broadened this to publish a screen of all null variants in all genes known to cause human disease in an autosomal dominant pattern to demonstrate the generalizability of our approach as well as to determine the frequency of occult dominant disease in an adult cohort). We are now completed a screen for all variants that cause disease in an autosomal recessive pattern and returned those through a web-portal. This enormous project (thousands of variants) has resulted in three publications. Evaluating the pathogenicity of variants identified above. A key challenge is to validate variants identified from sequencing and informatics approaches to determine if they are actually pathogenic. This can be done in a number of ways, including clinical phenotyping and pedigree analysis (as performed in HG300387-04). For the malignant hyperthermia project, we have convened an expert panel under ClinGen to evaluate all variants in RYR1 for MHS pathogenicity and develop a scoring method for future variants. Supporting other research groups by providing control data and phenotyping of controls. We have made ClinSeq variant data widely and openly accessible via dbSNP and dbGAP. We have also pioneered an extraordinary level of data sharing within the IRP by making all of our variants available to all staff by a web interface, which was launched in the fall of 2017. This has allowed a number of investigators to use our data as a comparison to measure the background frequency of variants is particular genes. This has led to the publication of a number of papers. We have completed deposition of our data into dbGaP. Finally, we measure the success of ClinSeq for the intramural program by the impact of the program on the wider research community. To that end, ClinSeq has served as the foundation for the development of the Intramural Research Program Clinical Center Genomics Opportunity, which has provided, through competitive applications, 1,200 exomes to be used by researchers outside of NHGRI to explore their phenotypes of interest and we are using the ClinSeq incidental findings analysis experience to develop a clinical incidental findings service for the CCGO program. We have completed sequencing of these samples and have met our timelines for this ambitious study. We have published a report summarizing the analysis and return of secondary variants in this cohort.